The field of the invention is related to methods for preventing and/or treating inflammatory somatic pain and chronic pain. More particularly the invention concerns the use of trimebutine [2-dimethylamino-2-phenylbutyl 3,4,5-trimethoxybenzoate hydrogen maleate] for preventing and/or treating inflammatory somatic pain as well as chronic pain.
Trimebutine [2-dimethylamino-2-phenylbutyl 3,4,5- trimethoxybenzoate hydrogen maleate; TMB] has been used in many countries since 1969 for the treatment of functional bowel disorders, including irritable bowel syndrome (IBS). The efficacy of the compound to relieve abdominal pain has been demonstrated in various clinical studies using different protocols of treatment (Lxc3xcttecke, 1980; Moshal and Herron, 1979, Toussaint et al., 1981; Ghidini et al. 1986). Trimebutine was found to display weak agonist activity for rat brain and guinea-pig (Roman et al., 1987) or canine (Allescher et al., 1991) intestinal opioid receptors, without selectivity for any of the xcexc-, xcex4- and xcexa-subtypes. This weak activity was confirmed when using isolated intestinal fragments under transmural stimulation (Pascaud et al., 1987). This property could be responsible for the modulatory action of trimebutine on intestinal motility in fasted dog. Trimebutine given either intravenously or orally delays the appearance of a phase III of the migrating motor complex (MMC) in the stomach and the duodenum by inducing a premature phase III, migrating along the whole intestine (Bueno et al., 1987). In man, trimebutine stimulates intestinal motility in both fed and fasted states (Grandjouan et al., 1989). Furthermore, trimebutine reverses the effect of stress in jejunal motility (Delis et al., 1994).
More recently, trimebutine has been shown to be able to influence the activity of visceral afferents by decreasing the intensity of the recto-colonic reflex in rats as evidenced by the inhibition of colonic motility consecutive to rectal distension (Julia et al., 1996). This result may be related to the beneficial effects found with trimebutine in patients with IBS and more specifically in the treatment of attacks of abdominal pain.
There is a general agreement (9th World Congress on Pain, Vienna, August 1999) that there is an unmet medical need for the treatment of chronic pain. NSAIDs and opiates are ineffective in many cases. Antidepressants are being used with inconsistent eficacy (50-60%). Certain anticonvulsants (carbamazepine, clonazepam, baclofen) may be active. In extreme cases, capsaicin and local anesthetics are being tried. However, none of these approaches is satisfactory and some patients are refractory to all of them. In some cases like trigeminal neuralgia, neurosurgery (differential thermocoagulation of Gasser ganglion) remains the only way of alleviating pain.
From a starting point in visceral pain, the inventors found, as confirmed in the present application, that trimebutine has an inhibitory action on glutamate release through the blockade of sodium channels. More particularly, they found that the inhibition of glutamate release follows a presynaptic mechanism of action even though the opioid properties of trimebutine are not involved in this mechanism. In addition, as shown through results obtained in certain in vivo models and more particularly in models of hyperalgesia and chronic pain, they demonstrate that trimebutine can have an action on pain conditions other than visceral pain. This confirmes that trimebutine is useful in the treatment and/or the prevention of hyperalgesia and chronic pain as well as inflammatory somatic pain.
The invention relates to the use of trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate] or its corresponding stereoisomers for the preparation of a medicament to prevent and/or treat inflammatory somatic pain and chronic pain. For the present invention, trimebutine is administered orally or by injection and preferably by intravenous injection at a dosage between 50 to 900 mg/day (patient with average weight of 70 kg) and preferentially between 300 to 600 mg/day. Particular embodiments of the invention provide the use of trimebutine or its stereoisomers for the preparation of medicaments useful for preventing and/or treating inflammatory somatic pain (for example arthritis, polyarthritis, spondylarthritis) and chronic pain conditions (for example neurological pain, osteo-traumatic pain, back pain, cancer pain, neuralgias including post-zosterian neuralgia). Specific embodiments concern a method for preventing and/or treating inflammatory somatic pain and/or chronic pain comprising administering trimebutine to a patient in need thereof